Pyrazole-amine compounds useful as kinase inhibitors

ABSTRACT

The present invention provides pyrazole derived compounds of formula (I)  
                 
 
useful for treating p38 kinase-associated conditions, where W, X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and m are as defined herein. The invention further pertains to pharmaceutical compositions containing at least one compound according to the invention useful for treating p38 kinase-associated conditions, and methods of inhibiting the activity of p38 kinase in a mammal.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a divisional application of U.S. Ser. No. 10/838,006, filed onMay 3, 2004, which claims the benefit of priority under 35 USC §119 ofU.S. patent application Ser. No. 60/467,029, filed May 1, 2003, theentire contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to pyrazole derived compounds useful for treatingp38 kinase-associated conditions. The invention further pertains topharmaceutical compositions containing at least one compound accordingto the invention useful for treating p38 kinase-associated conditions,and methods of inhibiting the activity of p38 kinase in a mammal.

BACKGROUND OF THE INVENTION

A large number of cytokines participate in the inflammatory response,including IL-1, IL-6, IL-8 and TNF-α. Overproduction of cytokines suchas IL-1 and TNF-α are implicated in a wide variety of diseases,including inflammatory bowel disease, rheumatoid arthritis, psoriasis,multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease,and congestive heart failure, among others [Henry et al., Drugs Fut.,Vol. 24 (1999), at pp. 1345-54; Salituro et al., Curr. Med. Chem., Vol.6 (1999), at pp. 807-823]. Evidence in human patients indicates thatprotein antagonists of cytokines are effective in treating chronicinflammatory diseases, such as, for example, monoclonal antibody toTNF-α (Enbrel) [Rankin et al., Br. J. Rheumatol., Vol. 34 (1995), at pp.334-42], and soluble TNF-α receptor-Fc fusion protein (Etanercept)[Moreland et al., Ann. Intern. Med., Vol. 130 (1999), at pp. 478-86].

The biosynthesis of TNF-α occurs in many cell types in response to anexternal stimulus, such as, for example, a mitogen, an infectiousorganism, or trauma. Important mediators of TNF-α production include themitogen-activated protein (MAP) kinases, a family of Ser/Thr proteinkinases that activate their substrates by phosphorylation. The MAPkinases are activated in response to various stress stimuli, includingbut not limited to proinflammatory cytokines, endotoxin, ultravioletlight, and osmotic shock.

One important MAP kinase is p38 kinase, also known as cytokinesuppressive anti-inflammatory drug binding protein (CSBP) or IK.Activation of p38 requires dual phosphorylation by upstream MAP kinasekinases (MKK3 and MKK6) on threonine and tyrosine within a Thr-Gly-Tyrmotif characteristic of p38 isozymes. There are four known isoforms ofp38, i.e., p38-α, p38β, p38γ, and p38δ. The α and β isoforms areexpressed in inflammatory cells and are key mediators of TNF-αproduction. Inhibiting the p38α and β enzymes in cells results inreduced levels of TNF-α expression. Also, administering p38α and βinhibitors in animal models of inflammatory disease has established theeffectiveness of p38 inhibitors in treating those diseases. The presentinvention provides pyrazole derived compounds, useful as kinaseinhibitors, in particular, as inhibitors of p38 kinase.

SUMMARY OF THE INVENTION

The present invention pertains to compounds having the formula (I), or apharmaceutically acceptable salt or solvate thereof, which compounds areuseful as kinase inhibitors, in particular, p38 kinase inhibitors:

wherein the symbols have the following meanings unless otherwiseindicated, and are, for each occurrence, independently selected:

-   ring G is phenyl or pyridyl;-   W is —NH(C═O)(CHR₈)_(r)-, —CH(R₈)NH—, —NHCH(R₈)—, —CH₂—O—, or    —(C═O)O—, wherein R₈ is hydrogen or alkyl, and r is 0, 1 or 2;-   R₁ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,    heteroaryl, substituted heteroaryl, cycloalkyl, substituted    cycloalkyl, heterocyclo or substituted heterocyclo, or —(C═O)R₁₈;-   R₂ is hydrogen, alkyl, substituted alkyl, alkoxy, substituted    alkoxy, amino, alkylamino, substituted alkylamino, cycloamino, or    substituted cycloamino;-   R₃ is hydrogen, trifluoromethyl, trifluoromethoxy, halogen, cyano,    nitro, C₁₋₄alkyl, substituted C₁₋₄alkyl, NR₁₁R₁₂, or OR₁₁;-   R₄ is hydrogen, C₁₋₄alkyl, substituted C₁₋₄alkyl, halogen,    trifluoromethyl, trifluoromethoxy, cyano, nitro, or OR₁₃;-   R₅ is at each occurrence independently selected from    trifluoromethyl, trifluoromethoxy, cyano, nitro, alkyl or    substituted alkyl, alkenyl or substituted alkenyl, alkynyl or    substituted alkynyl, cycloalkyl or substituted cycloalkyl,    heterocycle or substituted heterocycle, aryl or substituted aryl,    heteroaryl or substituted heteroaryl, OR₁₃, SR₁₃, S(═O)R₁₄,    S(═O)₂R₁₄, P(═O)₂R₁₄, S(═O)₂OR₁₅, P(═O)₂OR₁₄, NR₁₃R₁₄,    NR₁₃S(═O)₂R₁₅, NR₁₃P(═O)₂R₁₄, S(═O)₂NR₁₃R₁₄, P(═O)₂NR₁₃R₁₄,    C(=O)OR₁₃, C(═O)R₁₃, C(═O)NR₁₃R₁₄, OC(═O)R₁₃, OC(═O)NR₁₃R₁₄,    NR₁₃C(═O)OR₁₄, NR₁₆C(═O)NR₁₃R₁₄, NR₁₆S(═O)₂NR₁₃R₁₄,    NR₁₆P(═O)₂NR₁₃R₁₄, NR₁₃C(═O)R₁₄, and/or NR₁₃P(═O)₂R₁₄;-   X is —(C═O)NH—, —NH(C═O)—, —NH(C═O)O—, —SO₂NH—, —CO₂—, or is absent;-   R₆ is hydrogen, alkyl or substituted alkyl, alkoxy or substituted    alkoxy, phenoxy or substituted phenoxy, cycloalkyl or substituted    cycloalkyl, heterocycle or substituted heterocycle, aryl or    substituted aryl, heteroaryl or substituted heteroaryl; or where X    is absent, R₆ can be halogen, cyano, trifluoromethyl, alkyl, amino,    or alkylamino; or alternatively, R₆ is joined together with a group    R₅ on an adjacent carbon atom to form an optionally-substituted,    fused five to six membered heterocyclic or carbocyclic ring;-   R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆ and R₁₇ are independently at each    occurrence selected from hydrogen, alkyl, substituted alkyl,    cycloalkyl or substituted cycloalkyl, heterocycle or substituted    heterocycle, aryl or substituted aryl, and heteroaryl or substituted    heteroaryl, except R₁₅ is not hydrogen;-   R₁₈ is hydrogen, alkyl or substituted alkyl, alkenyl or substituted    alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted    cycloalkyl, heterocycle or substituted heterocycle, heteroaryl, or    substituted heteroaryl, aryl or substituted aryl; and-   m is 0, 1, 2 or 3; or a pharmaceutically-acceptable salt, hydrate,    solvent, isomer, or prodrug thereof.

FURTHER DESCRIPTION OF THE INVENTION

Further aspects of the invention will be apparent to one skilled in thefield upon reading the disclosure herein.

Definitions

The following are definitions of terms used in the present specificationand claims. The initial definition provided for a group or term hereinapplies to that group or term throughout the present specification andclaims herein individually or as part of another group, unless otherwiseindicated.

The terms “alkyl” and “alk” refer to a straight or branched chain alkane(hydrocarbon) radical containing from 1 to 12 carbon atoms, preferably 1to 6 carbon atoms. Exemplary “alkyl” groups include methyl, ethyl,propyl, isopropyl, 1-methylpropyl, n-butyl, t-butyl, isobutyl, pentyl,hexyl, isohexyl, heptyl, dimethylpentyl, diethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. Theterm “C₁-C₄ alkyl” refers to a straight or branched chain alkane(hydrocarbon) radical containing from 1 to 4 carbon atoms, such asmethyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl. Alower alkyl is a “C₁-C₄ alkyl.” When alkyl, lower alkyl (or C₁-C₄alkyl)is used as a suffix following another named group, such as“hydroxyalkyl” or hydroxyl(lower alkyl), this is intended to refer to analkyl or lower alkyl (C₁-C₄alkyl) having bonded thereto one, two orthree of the other, specifically-named group(s) at any point ofattachment on either the straight or branched chain of the alkyl. As afurther example, arylalkyl includes groups such as benzyl orphenylethyl. When the term “substituted” is used with such groups, as in“substituted arylalkyl” or “substituted alkoxyalkyl,” it should beunderstood that either the alkyl moiety, the other named moiety, orboth, may be substituted with groups selected from those recited hereinas appropriate, e.g., for the alkyl moiety, groups may be selected fromthose recited below for substituted alkyl, and for the other,specifically-named group, groups may be selected from those recitedbelow for that group.

“Substituted alkyl” refers to an alkyl group as defined abovesubstituted with one or more substituents, preferably 1 to 4substituents, more preferably 1 to 2 substitutents, at any availablepoint of attachment on the straight and/or branched chain. Exemplarysubstituents may include but are not limited to one or more of halogen,haloalkyl (e.g., a single halo substituent or multiple halosubstitutents forming, in the latter case, groups such as aperfluoroalkyl group including for example, —CHCl₂ and/or CF₃),haloalkoxyl (e.g., including trifluoromethoxy), cyano, nitro, alkenyl,alkynyl, cycloalkyl, heterocycle, heteroaryl, aryl, OR_(a), SR_(a),S(═O)R_(e), S(═O)₂R_(e), P(═O)₂R_(e), S(═O)₂OR_(e), P(═O)₂OR_(e),P(═O)(OR)₂, NR_(b)R_(c), NR_(b)S(═O)₂R_(e), NR_(b)P(═O)₂R_(e),S(═O)₂NR_(b)R_(c), P(═O)₂NR_(b)R_(c), C(═O)OR_(a), C(═O)R_(a),C(═O)NR_(b)R_(c), OC(═O)R_(a), C(═O)ONR_(b)R_(c), OC(═O)NR_(b)R_(c),NR_(b)C(═O)OR_(a), NR_(d)C(═O)NR_(b)R_(c), NR_(d)S(═O)₂NR_(b)R_(c),NR_(d)P(═O)₂NR_(b)R_(c), NR_(b)C(═O)R_(a), and/or NR^(b)P(═O)₂R_(e),wherein R_(a), R_(b), R_(c), R_(d) and R_(e) are selected from hydrogen,alkyl, alkenyl, aminoalkyl, alkylaminoalkyl, cycloalkyl(alkyl),aryl(alkyl), heterocyclo(alkyl), heteroaryl(alkyl), cycloalkyl, aryl,heterocyclo, and/or heteroaryl, except R_(e) is not hydrogen; andadditionally, when R_(b) and R_(c) are attached to the same nitrogenatom, they may be joined together to form a cycloamino group. Each ofR_(a), R_(b), R_(c), R_(d) and/or R_(e) on the alkyl and/or cyclicmoieties in turn may be optionally substituted with one to three groups,preferably substituted with up to two groups (0 to 2 groups), selectedfrom lower alkyl, lower alkenyl, R_(f), and a lower alkyl or loweralkenyl substituted with one to two R_(f), wherein R_(f) is selectedfrom one or more of cyano, halogen, haloC₁-C₄alkyl, haloC₁-C₄alkoxy,keto (═O) (where valence allows), nitro, OH, O(C₁-C₄alkyl), SH,S(C₁-C₄alkyl), S(═O)(C₁-C₄alkyl), S(═O)₂(C₁-C₄alkyl), NH₂,NH(C₁-C₄alkyl), N(C₁-C₄alkyl)₂, NH(cycloalkyl), NH(phenyl), phenyl,benzyl, phenoxy, benzyloxy, NHS(═O)₂(alkyl), S(═O)₂NH₂,S(═O)₂NH(C₁-C₄alkyl), S(═O)₂N(C_(1-C) ₄alkyl)₂, S(═O)₂NH(cycloalkyl),S(═O)₂NH(phenyl), C(═O)OH, C(═O)O(C₁-C₄alkyl), C(═O)H,C(═O)(C₁-C₄alkyl), C(═O)NH₂, C(═O)NH(C₁-C₄alkyl), C(═O)N(C₁-C₄alkyl)₂,C(═O)NH(cycloalkyl), C(═O)NH(phenyl), C(═O)ONH₂, C(═O)ONH(C₁-C₄alkyl),C(═O)ON(C₁-C₄alkyl)₂, C(═O)ONH(cycloalkyl), C(═O)ONH(phenyl),NHC(═O)OC₁-C₄alkyl, N(C₁-C₄alkyl)C(═O)O(C₁-C₄alkyl), NHC(═O)NH₂,NHC(═O)NH(C₁-C₄alkyl), NHC(═O)N(C₁-C₄alkyl)₂, NHC(═O)NH(cycloalkyl),NHC(═O)NH(phenyl), NHC(═O)H, and/or NHC(═O)(C₁-C₄alkyl).

The term “alkenyl” refers to a straight or branched chain hydrocarbonradical containing from 2 to 12 carbon atoms and at least onecarbon-carbon double bond. Exemplary such groups include ethenyl andallyl. Lower alkenyl means an alkenyl group of 2 to 4 carbon atoms.“Substituted alkenyl” refers to an alkenyl group substituted with one ormore substituents, preferably 1 to 4 substituents, more preferably 1 to2 substituents, at any available point of attachment. Exemplarysubstituents may include, but are not limited to, alkyl, substitutedalkyl, and those groups recited above as exemplary substituents forsubstituted alkyl groups.

The term “alkynyl” refers to a straight or branched chain hydrocarbonradical containing from 2 to 12 carbon atoms and at least onecarbon-to-carbon triple bond. Exemplary such groups include ethynyl.“Substituted alkynyl” refers to an alkynyl group substituted with one ormore substituents, preferably 1 to 4 substituents, more preferably 1 to2 substituents, at any available point of attachment. Exemplarysubstituents include, but are not limited to, alkyl, substituted alkyl,and those groups recited above as exemplary substituents for substitutedalkyl groups.

The term “alkoxy” refers to the group OR_(g), wherein R_(g)is selectedfrom alkyl, alkenyl, or cycloalkyl. A C₁-C₄alkoxy is an alkoxy groupOR_(g′) wherein R_(g′) is a C₁-C₄alkyl or C₃-C₄cycloalkyl. A substitutedalkoxy group is an alkoxy group as defined above wherein at least one ofthe alkyl, alkenyl, and/or cycloalkyl moieties is substituted with oneor more, preferably 1 to 4, more preferably 1 to 2, groups selected fromthose recited above for substituted alkenyl groups.

The term “amino” refers to NH₂, and an alkylamino refers to an aminogroup wherein one or both of the hydrogen atoms is or are replaced witha group chosen from alkyl, alkenyl, and/or cycloalkyl. Thus, alkylaminorefers to the group NR_(h)R_(i), wherein R_(h) and R_(i) are selectedfrom hydrogen, alkyl, alkenyl, and/or cycloalkyl, provided R_(h) andR_(i) are not both hydrogen. “Aminoalkyl” refers to an alkyl group asdefined above substituted with an amino group, and an “alkylaminoalkyl”refers to an alkyl group as defined above substituted with one or morealkylamino groups. A substituted alkylamino group is an alkylamino groupwherein at least one of the alkyl, alkenyl, and/or cycloalkyl moietiesis substituted with one or more, preferably 1 to 4, more preferably 1 to2, groups selected from those recited herein as appropriate for therecited moeity. Thus, for example, an optionally-substituted alkylaminogroup refers to the group —NR′R″, wherein R′ and R″ are selected fromhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,cycloalkyl, and substituted cycloalkyl, provided R′ and R″ are not bothhydrogen, as in that case the group is amino and notoptionally-substituted alkylamino.

A cycloamino group refers to a group —NR′R″, wherein R′ and R″ join toform a monocyclic heterocyclo ring, such as, for example, N-morpholinyl,N-piperidinyl, N-piperazinyl and the like. A “substituted cycloamino” isa cycloamino group having one or more, preferably one to 4, morepreferably one to 2, substituents selected from those recited below forsubstituted heterocyclo groups.

The term “alkylthio” refers to the group SR_(g), wherein R_(g) isselected from alkyl, alkenyl, and cycloalkyl. A C₁-C₄alkylthio is analkylthio group SR_(g′) wherein R_(g′) is a C₁-C₄alkyl orC₃-C₄cycloalkyl. A substituted alkylthio group is an alkylthio groupwherein at least one of the alkyl, alkenyl, and/or cycloalkyl moietiesis substituted with one or more, preferably 1 to 4, more preferably 1 to2, groups selected from those recited above for substituted alkenylgroups.

The term “aryl” refers to cyclic, aromatic hydrocarbon groups which have1 to 3 aromatic rings, including phenyl and naphthyl. The aryl group mayhave fused thereto a second or third ring which is a heterocyclo,cycloalkyl, or heteroaryl ring, provided in that case the point ofattachment will be to the aryl portion of the ring system. Thus,exemplary aryl groups include,

and so forth.

“Substituted aryl” refers to an aryl group substituted by one or moresubstituents, preferably 1 to 3 substituents, more preferably 1 to 2substituents, at any point of attachment of the aryl ring and/or of anyfurther ring fused thereto. Exemplary substituents include, but are notlimited to, alkyl, substituted alkyl, and where valence allows thosegroups recited above as exemplary substituents for substituted alkylgroups.

The term “cycloalkyl” refers to a fully saturated and partiallyunsaturated cyclic hydrocarbon group containing from 1 to 3 rings and 3to 8 carbons per ring. Exemplary such groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, etc. A cycloalkyl ring may have a carbonring atom replaced with a carbonyl group (C═O), as illustrated below.Cycloalkyl groups include such rings having a second or third ring fusedthereto that is a heterocyclo, heteroaryl, or aryl group, provided thatin such cases the point of attachment is to the cycloalkyl portion ofthe ring system. The term “cycloalkyl” also includes such rings having asecond or third ring attached to the ring or ring system in a spirofashion wherein the spiro ring is either a heterocyclo or carbocyclicring. “Substituted cycloalkyl” refers to a cycloalkyl group as definedabove having one or more substituents, preferably 1 to 4 substituents,more preferably 1 to 2 substituents, at any available point ofattachment on either the cycloalkyl ring and where valence allows on anyrings fused or attached thereto. Exemplary substituents include, but arenot limited to, alkyl, substituted alkyl, and those groups recited aboveas exemplary substituents for substituted alkyl groups.

Thus, as an illustration non-limiting examples of cycloalkyl rings mayinclude,

and the like.

The terms “heterocycle,” “heterocyclic” and “heterocyclo” refer to fullysaturated or partially unsaturated non-aromatic cyclic groups (forexample, 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to16 membered tricyclic ring systems) which have at least one heteroatomin at least one carbon atom-containing ring. Each ring of theheterocyclic group containing a heteroatom may have 1, 2, 3, or 4heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfuratoms, where the nitrogen and/or sulfur heteroatoms may optionally beoxidized and the nitrogen heteroatoms may optionally be quaternized. Aheterocyclo ring may have a carbon ring atom replaced with a carbonylgroup (C═O), as illustrated above for cycloalkyl groups. Theheterocyclic group may be attached to the remainder of the molecule atany nitrogen atom or carbon atom of the ring or ring system.Additionally, the heterocyclo group may have a second or third ringattached thereto in a spiro or fused fashion, provided the point ofattachment is to the heterocyclo group. An attached spiro ring may be acarbocyclic or heterocyclic ring and the second and/or third fused ringmay be a cycloalkyl, aryl or heteroaryl ring. Exemplary monocyclicheterocyclic groups include azetidinyl, pyrrolidinyl, pyrazolinyl,imidazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl,tetrahyrdofuryl, tetrahydropyranyl, thiamorpholinyl, and the like.

Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl,quinuclidinyl, benzopyrrolidinyl, benzopyrazolinyl, benzoimidazolidinyl,benzopiperidinyl, benzopiperazinyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, dihydroisoindolyl and the like.

“Substituted heterocycle,” “substituted heterocyclic,” and “substitutedheterocyclo” refer to heterocycle, heterocyclic or heterocyclo groupssubstituted with one or more substituents, preferably 1 to 4substituents, more preferably 1 to 2 substituents, at any availablepoint of attachment to the heterocyclo ring and/or any ring fused orattached thereto in a spiro fashion. Exemplary substituents include, butare not limited to, alkyl, substituted alkyl, and those groups recitedabove as exemplary substituents for substituted alkyl groups.

The term “heteroaryl” refers to aromatic cyclic groups (for example, 5to 6 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 16membered tricyclic ring systems) which have at least one heteroatom inat least one carbon atom-containing ring. Each ring of the heteroarylgroup containing a heteroatom may have 1, 2, 3, or 4 heteroatomsselected from nitrogen atoms, oxygen atoms and/or sulfur atoms, wherethe nitrogen and/or sulfur heteroatoms may optionally be oxidized andthe nitrogen heteroatoms may optionally be quaternized. (The term“heteroarylium” refers to a heteroaryl group bearing a quaternarynitrogen atom and thus a positive charge.) The heteroaryl group may beattached to the remainder of the molecule at any nitrogen atom or carbonatom of the ring or ring system. Additionally, the heteroaryl group mayhave a second or third carbocyclic (cycloalkyl or aryl) or heterocyclicring fused thereto provided the point of attachment is to the heteroarylgroup.

Exemplary monocyclic heteroaryl groups include pyrazolyl, imidazolyl,triazolyl, oxazolyl, furyl, thiazolyl, isoxazolyl, thiazolyl, pyridyl[i.e.,

pyridazinyl [i.e.,

pyrimidinyl [i.e.,

pyrazinyl [i.e.,

triazinyl, and the like. Unless reference is made to a specific point ofattachment, e.g., as in pyrid-2-yl, pyridazin-3-yl, it is intended thatsuch heteroaryl groups can be bonded to another moiety at any availablepoint of attachment.

Exemplary bicyclic heteroaryl groups include benzothiazolyl,benzoxazolyl, benzoxadiazolyl, benzothienyl, quinolinyl, chromenyl,indolyl, indazolyl, isoquinolinyl, benzimidazolyl, benzopyranyl,benzofuryl, benzofurazanyl, benzopyranyl, cinnolinyl, quinoxalinyl,pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl,furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), triazinylazepinyl, andthe like.

“Substituted heteroaryl” refers to heteroaryl groups substituted withone or more substituents as valence allows, preferably 1 to 3substituents, more preferably 1 to 2 substituents, at any availablepoint of attachment to the heteroaryl ring and/or any ring fusedthereto. Exemplary substituents include, but are not limited to, alkyl,substituted alkyl, and those groups recited above as exemplarysubstituents for substituted alkyl groups.

When reference is made to an optionally-substituted, specifically-namedaryl, heteroaryl, cycloalkyl, or heterocyclo ring, the optionalsubstituents may be selected as valence allows from the groups recitedabove for the genus of rings of which the specifically-named group is amember. For example, “optionally-substituted phenyl” includesunsubstituted phenyl rings as well as phenyl rings containing one ormore substituents selected from those recited above for aryl groups.“Optionally-substituted pyridyl, pyridazinyl, pyrimidinyl, andpyrazinyl,” includes unsubstituted pyridyl, pyridazinyl, pyrimidinyl,and pyrazinyl rings, as well as such rings containing one or moresubstituents selected from those recited above for heteroaryl groups.

The term “optionally substituted oxadiazolyl” as used herein is intendedto refer to the group,

wherein R_(j) is selected from a substituent recited above forsubstituted heteroaryl groups.

The term “quaternary nitrogen” refers to a tetravalent positivelycharged nitrogen atom including, for example, the positively chargednitrogen in a tetraalkylammonium group (e.g., tetramethylammonium,N-methylpyridinium), the positively charged nitrogen in protonatedammonium species (e.g., trimethyl-hydroammonium, N-hydropyridinium), thepositively charged nitrogen in amine N-oxides (e.g.,N-methyl-morpholine-N-oxide, pyridine-N-oxide), and the positivelycharged nitrogen in an N-amino-ammonium group (e.g., N-aminopyridinium).

The terms “halogen” or “halo” refer to chlorine, bromine, fluorineand/or iodine.

The term haloalkyl refers to an alkyl group having a single halosubstituent or multiple halo substitutents forming, for example, groupssuch as a perfluoroalkyl group including trichloromethyl ortrifluoromethyl (CCl₃ or CF₃). A haloC₁-C₄alkyl refers to a C₁-C₄alkylhaving one or more halo substituents.

The term haloalkoxy refers to an alkoxy group as defined above whereinthe alkyl moiety has a single halo substituent or multiple halosubstitutents forming, for example, groups such as a trifluoromethoxy. AhaloC₁-C₄alkoxy refers to a C₁-C₄alkoxy having one or more halosubstituents.

The term “saturated” when used herein is intended to refer to fullysaturated and partially saturated moieties, and conversely,“unsaturated” refers to fully unsaturated and partially unsaturatedmoieties.

When a functional group is termed “protected”, this means that the groupis in modified form to mitigate, especially preclude, undesired sidereactions at the protected site. Suitable protecting groups for themethods and compounds described herein include, without limitation,those described in standard textbooks, such as Greene, T. W. et al.,Protective Groups in Organic Synthesis, Wiley, N.Y. (1999).

The term “selective” as used herein with reference to the capability ofthe claimed compounds to inhibit p38 activity means that the compound inquestion has a level of activity as measured in enzyme assays forinhibiting the p38α/β kinase that is significantly greater than theactivity of the compound in inhibiting a plurality of other kinasesfalling within families throughout the human kinome. The term“significantly greater activity” includes the activity of at least onecompound having about 500-fold or more greater activity for inhibitingp38α/β enzyme as compared with the activity of the compound ininhibiting other kinases, for example, as compared with the activity ofthe compound in inhibiting about twenty-five or more other kinases, inanother example, as compared with about fifty or more other kinases, andin yet another example, as compared with about 100 or more otherkinases. Thus, a selective p38 inhibitor as defined herein according toone embodiment will inhibit the α-isoform of the p38 kinase, theβ-isoform of the p38 kinase, and/or both the α and β forms of the p38kinase, at least 500 times greater than it will inhibit any one of aplurality of other kinases. Thus, for example, considering an embodimentinvolving comparison with a sample of twenty-five other kinases, p38selective compounds will have 500 times greater activity in inhibitingp38α/β kinase as compared with any one of each of the twenty-five otherkinases considered individually (e.g., in a one-on-one comparison). Inanother embodiment of the invention, compounds are provided having atleast about 1,000-fold greater activity for inhibiting p38α/β kinase ascompared with other kinases, for example, as compared with abouttwenty-five or more, about fifty or more, and in yet another example, ascompared with about 100 or more other kinases. In yet another embodimentof the invention, compounds are provided having at least about5,000-fold greater activity for inhibiting p38α/β kinase as comparedwith other kinases, for example, as compared with about twenty-five ormore other kinases, as compared with about fifty or more other kinases,and in yet another example, as compared with about 100 or more otherkinases. The term “highly selective” as used herein means the compoundin question has at least about 10,000 fold greater activity forinhibiting the p38α/β kinase enzyme as compared with at least thirtyother kinases, more preferably, as compared with at least about fifty ormore other kinases. When reference is made herein to “other kinases”,applicant intends to refer to kinases known in the field other than thep38α/β kinases. For example, various known kinases and kinase familiesother than the 38α/β kinase are identified in WO 02/062804, and inManning, G. et al., “The Protein Kinase Complement of the Human Genome”,Science (Washington, D.C., United States) (2002), 298(5600), at pp.1912-1916, 1933-1934, which is incorporated herein by reference. “Otherkinases” as idenfitied therein thus may include, without limitation, oneor more kinases chosen from the following kinases and/or kinasefamilies: CaMK1, CaMK2, CDK, DAPK, EMT, FGF, FMS, GSK3, LCK, PDGF-R,PKA, PCK, RAF, RIPK, LIMK-1, SYK, Met, PAK-4, PAK-5, ZC-1, STLK-2,DDR-2, Aurora 1, Aurora 2, Bub-1, PLK, Chk1, Chk2, HER_(2,) JAK, raf1,MEK1, EGF-R, RSK/RSK, IGF-R, IRAK, VEGF-R, P13K, PDK, HIPK, STKR, BRD,Wnk, NKF3, NKF4, NKF5, weel kinase, Src, Ab1, ILK, MK-2, IKK-2, RIPK,Cdc7, Ste11, Ste20, Ste7, Tec, Trk, and/or Nek, and so forth. The aboveis an exemplary, non-limiting list of other kinases. Manning identified518 protein kinases, and applicant intends to incorporate each one ofthese 518 protein kinases other than the p38 kinase in the definition ofthe term “other kinases” as used herein.

There are many enzyme assays known in the field that may be used tomeasure the levels of activity to determine selectivity. Applicant hasdescribed certain enzyme assays below but does not intend to be limitedto use of these specific assays with regard to the definition ofselectivity herein.

Unless otherwise indicated, a heteroatom with an unsatisfied valence isunderstood to have hydrogen atoms sufficient to satisfy the valences, asone skilled in the field will appreciate.

The compounds of formula I may form salts which are also within thescope of this invention. Reference to a compound of the formula I hereinis understood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic and/orbasic salts formed with inorganic and/or organic acids and bases. Inaddition, when a compound of formula I contains both a basic moiety,such as but not limited to a pyridine or imidazole, and an acidic moietysuch as but not limited to a carboxylic acid, zwitterions (“innersalts”) may be formed and are included within the term “salt(s)” as usedherein. Pharmaceutically acceptable (i.e., non-toxic, physiologicallyacceptable) salts are preferred, although other salts may also beuseful, e.g., in isolation or purification steps which may be employedduring preparation. Salts of the compounds of the formula I may beformed, for example, by reacting a compound I with an amount of acid orbase, such as an equivalent amount, in a medium such as one in which thesalt precipitates or in an aqueous medium followed by lyophilization.

The compounds of formula I which contain a basic moiety, such as but notlimited to an amine or a pyridine or imidazole ring, may form salts witha variety of organic and inorganic acids. Exemplary acid addition saltsinclude acetates (such as those formed with acetic acid or trihaloaceticacid, for example, trifluoroacetic acid), adipates, alginates,ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates,borates, butyrates, citrates, camphorates, camphorsulfonates,cyclopentanepropionates, digluconates, dodecylsulfates,ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates,hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides,hydroiodides, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonates),lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g.,2-naphthalenesulfonates), nicotinates, nitrates, oxalates, pectinates,persulfates, phenylpropionates (e.g., 3-phenylpropionates), phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates (such as thosementioned herein), tartrates, thiocyanates, toluenesulfonates such astosylates, undecanoates, and the like.

The compounds of formula I which contain an acidic moiety, such as butnot limited to a carboxylic acid, may form salts with a variety oforganic and inorganic bases. Exemplary basic salts include ammoniumsalts, alkali metal salts such as sodium, lithium and potassium salts,alkaline earth metal salts such as calcium and magnesium salts, saltswith organic bases (for example, organic amines) such as benzathines,dicyclohexylamines, hydrabamines (formed withN,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines,N-methyl-D-glycamides, t-butyl amines, and salts with amino acids suchas arginine, lysine and the like. Basic nitrogen-containing groups maybe quaternized with agents such as lower alkyl halides (e.g. methyl,ethyl, propyl, and butyl chlorides, bromides and iodides), dialkylsulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates), longchain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides), aralkyl halides (e.g. benzyl and phenethylbromides), and others.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug” as employed herein denotes acompound which, upon administration to a subject, undergoes chemicalconversion by metabolic or chemical processes to yield a compound of theformula I, or a salt and/or solvate thereof. Solvates of the compoundsof formula I include, for example, hydrates.

Compounds of the formula I, and salts thereof, may exist in theirtautomeric form (for example, as an amide or imino ether). All suchtautomeric forms are contemplated herein as part of the presentinvention.

All stereoisomers of the present compounds (for example, those which mayexist due to asymmetric carbons on various substituents), includingenantiomeric forms and diastereomeric forms, are contemplated within thescope of this invention. Individual stereoisomers of the compounds ofthe invention may, for example, be substantially free of other isomers(e.g., as a pure or substantially pure optical isomer having a specifiedactivity), or may be admixed, for example, as racemates or with allother, or other selected, stereoisomers. The chiral centers of thepresent invention may have the S or R configuration as defined by theIUPAC 1974 Recommendations. The racemic forms can be resolved byphysical methods, such as, for example, fractional crystallization,separation or crystallization of diastereomeric derivatives orseparation by chiral column chromatography. The individual opticalisomers can be obtained from the racemates by any suitable method,including without limitation, conventional methods, such as, forexample, salt formation with an optically active acid followed bycrystallization.

All configurational isomers of the compounds of the present inventionare contemplated, either in admixture or in pure or substantially pureform. The definition of compounds of the present invention embraces bothcis (Z) and trans (E) alkene isomers, as well as cis and trans isomersof cyclic hydrocarbon or heterocyclo rings.

When reference is made herein to a compound of formula (I) herein, thisis intended to refer to each compound of formula (I), and each salt,prodrug, solvate, or isomer thereof, alone or in combination with othercompounds of formula (I), other salts, prodrugs, solvates, or isomers ofcompounds of formula (I), or other compounds not of formula (I), withoutlimitation to the manner in which said compound of formula (I), or salt,prodrug, solvate, or isomer thereof is made or formed, for example,whether existing in a pure form, isolated form, crude form, togetherwith one or more excipients or impurities, existing in a solid or liquidform, in a pharmaceutical preparation before administration to apatient, as formed in the body of a patient after administration to apatient, and so forth.

Throughout the specification, groups and substituents thereof may bechosen to provide stable moieties and compounds.

Alternate Embodiments

According to one aspect of the invention, compounds are providing havingthe formula,

wherein:

-   ring G is phenyl or pyridyl;-   W is —NH(C═O)—, —CH₂NH—, —NHCH₂—, —CH₂—O—, or —(C═O)O—;-   R₁ is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,    or substituted heteroaryl;-   R₂ is hydrogen, alkyl, substituted alkyl, alkoxy, substituted    alkoxy, amino, alkylamino, substituted alkylamino, cycloamino, or    substituted cycloamino;-   R₃ is hydrogen or lower alkyl;-   R₄ is hydrogen, C₁₋₄alkyl, or halogen;-   R₅ is as defined previously in the summary of invention;-   X is —(C═O)NH—, or is absent;-   R₆ is hydrogen, alkyl or substituted alkyl, cycloalkyl or    substituted cycloalkyl, heterocycle or substituted heterocycle,    heteroaryl or substituted heteroaryl; or alternatively, R₆ is joined    together with a group R₅ on an adjacent carbon atom to form an    optionally-substituted, fused five to six membered heterocyclic or    carbocyclic ring; and-   m is 0, 1, or 2; or a pharmaceutically-acceptable salt, hydrate,    solvent, isomer, or prodrug thereof.

According to another aspect of the invention, compounds are providedhaving the formula,

According to another aspect of the invention, compounds are providedwherein W is —NH(C═O)—.

According to another aspect of the invention, compounds are providedwherein W is —CH₂NH— or —NHCH₂—.

According to another aspect of the invention, compounds are providedwherein W is —CH₂—O—, or —(C═O)O—.

According to another aspect of the invention, compounds are providedhaving the formula,

wherein R₉ is selected from alkyl or substituted alkyl, trifluoromethyl,trifluoromethoxy, halogen, cyano, nitro, OH, OR₁₀, SR₁₀, and S(═O)₂R₁₀,wherein R₁₀ is lower alkyl; and n is 0, 1, 2 or 3.

According to another aspect of the invention, compounds are providedwherein:

-   Q is phenyl or pyridyl;-   R₆ is C₁-C₄ alkyl or substituted C₁-C₄ alkyl, cycloalkyl or    substituted cycloalkyl;-   R₂ is lower alkyl, amino, or alkylamino; and-   R₄ is lower alkyl or halogen.

According to another aspect of the invention, compounds are providedwherein:

-   R₁ is C₁-C₄ alkyl or substituted C₁-C₄ alkyl, cycloalkyl or    substituted cycloalkyl, heterocycle or substituted heterocycle, aryl    or substituted aryl;-   R₆ is cyclopropyl;-   R₂ is hydrogen, trifluoromethyl, halogen, C₁-C₄ alkyl or substituted    C₁-C₄ alkyl, NR₇R_(8,) or OR₈;-   R₃ is hydrogen, C₁-C₄ alkyl or substituted C₁-C₄ alkyl;-   R₄ is lower alkyl or halogen; and-   m is 0-1.

According to another aspect of the invention, compounds are providedwherein R₃ is hydrogen and R₄ is methyl.

According to another aspect of the invention, compounds are providedwherein one of R₅ and R₆ form a heteroaryl so that ring Q is a groupselected from:

wherein p is 0, 1 or 2; and/or pharmaceutically-acceptable salts,prodrugs, solvates, isomers, and/or hydrates thereof.

According to another aspect of the invention, compounds are providedwherein R₁ is selected from:

-   R₃₀, R₃₁, R₃₂, R₃₃ and R₃₄ are selected from hydrogen, halogen,    cyano, trifluoromethyl, trifluoromethoxy, C₁₋₄alkyl, O(C₁₋₄alkyl),    nitro, and/or SO₂CH₃; and-   R₅₀ is hydrogen, alkyl, or arylalkyl; and n is at each occurrence    independently selected from 0-3; and/or pharmaceutically-acceptable    salts, prodrugs, solvates, isomers, and/or hydrates thereof.

According to another aspect of the invention, compounds are providedwherein

-   R₁ is optionally-substituted aryl or heteroaryl;-   R₂ is hydrogen, lower alkyl, halogen, haloalkyl, trifluoromethyl,    NH₂, NH(alkyl), NH(cycloalkyl), N(alkyl)₂, or —CH₂—O—CH₃, wherein    each of said alkyl groups of NH(alkyl), and/or N(alkyl)₂, are in    turn optionally substituted with one to two of OH, O(C₁₋₄alkyl),    imidazolyl, pyridyl, phenyl, tetrahydrofuryl, NH₂, NH(alkyl),    N(alkyl)₂, and/or N-morpholinyl;-   R₃ is hydrogen or methyl;-   R₄ is methyl or halogen;-   X is —C(═O)NH— or is absent;-   R₆ is lower alkyl or cyclopropyl, or when X is absent, R₆ is    optionally-substituted heteroaryl; and-   m is 0 or 1; and/or pharmaceutically-acceptable salts, prodrugs,    solvates, isomers, and/or hydrates thereof.

According to another aspect of the invention, compounds are providedwherein R₆ is selected from the group consisting of:

wherein R₂₀ is hydrogen, lower alkyl or phenyl.

According to another aspect of the invention, compounds are providedhaving the formula,

wherein,

-   R₂ is hydrogen, lower alkyl, halogen, haloalkyl, trifluoromethyl,    NH₂, NH(alkyl), NH(cycloalkyl), N(alkyl)₂, or —CH₂—O—CH₃, wherein    each of said alkyl groups of NH(alkyl), and/or N(alkyl)₂, are in    turn optionally substituted with one to two of OH, O(C₁₋₄alkyl),    imidazolyl, pyridyl, phenyl, tetrahydrofuryl, NH₂, NH(alkyl),    N(alkyl)₂, and/or N-morpholinyl;-   R₄ is methyl or halogen;-   X is —C(═O)NH— or is absent;-   R₆ is lower alkyl or cyclopropyl, or when X is absent, R₆ is    optionally-substituted heteroaryl;-   R₉ is selected from alkyl or substituted alkyl, trifluoromethyl,    trifluoromethoxy, halogen, cyano, nitro, OH, OR₁₀, SR₁₀, and    S(═O)₂R₁₀, wherein R₁₀ is lower alkyl;-   m is 0 or 1; and-   n is 0, 1, 2 or 3; and/or pharmaceutically-acceptable salts,    prodrugs, solvates, isomers, and/or hydrates thereof.

Further aspects of the invention may be apparent to one skilled in thefield upon reading the disclosure herein, e.g., considering the examplesbelow.

Utility

The compounds of the invention are selective inhibitors of p38 kinase,and in particular, isoforms p38α and p38β. Accordingly, compounds offormula (I) have utility in treating conditions associated with p38kinase activity. Such conditions include diseases or disorders in whichcytokine levels are modulated as a consequence of intracellularsignaling via p38, and in particular, diseases that are associated withan overproduction of cytokines IL-1, IL-4, IL-8, and TNF-α. As usedherein, the terms “treating” or “treatment” encompass responsive and/orprophylaxis measures addressed to the disease state and/or its sypmtoms,e.g., measures designed to inhibit or delay the onset of the disease ordisorder, achieve a full or partial reduction of the symptoms or diseasestate, and/or alleviate, lessen, or cure the disease and/or itssymptoms. When reference is made herein to inhibition of “p-38α/βkinase,” this means that either or both p38α and p38β kinase areinhibited.

In view of their activity as inhibitors of p-38α/β kinase, compounds ofFormula (I) are useful in treating inflammatory diseases, autoimmunediseases, destructive bone disorders, proliferative disorders,angiogenic disorders, infectious diseases, neurodegenerative diseases,viral diseases, and ischemia reperfusion conditions.

More particularly, the inventive compounds may be used to treatinflammatory diseases including, but not limited to, arthritis (e.g.,rheumatoid arthritis, lyme disease arthritis, osteoarthritis, traumaticarthritis, rubella arthritis, psoriatic arthritis, gouty arthritis, andother arthritic conditions); glomerulonephritis, pancreatitis (acute orchronic), diabetes, diabetic retinopathy, macular degeneration,conjunctivitis, aplastic anemia, thrombocytopenia, gastritis, chronicthyroiditis, chronic active hepatitis, multiple sclerosis, inflammatorybowel disease, ulcerative colitis, Crohn's disease, cachexia (includingcachexia secondary to infection, cancer, or heart disease), periodontaldisease, Alzheimer's disease, Parkinson's disease, keloid formation,pulmonary sarcoidosis, myasthenia gravis, inflammatory reaction inducedby endotoxin, Reiter's syndrome, gout, acute synovitis, diseasescharacterized by massive neutrophil infiltration, ankylosingspondylitis, influenze, cerebral malaria, silicosis, bone resorptiondisease, fever, myalgias due to infection, osteoporosis, multiplemyeloma-related bone disorder, neurodegenerative disease caused bytraumatic injury, and traumatic brain injury.

The inventive compounds may also be used to treat acute or chronic graftvs host reactions (e.g., pancreatic islet allograft), acute or chronictransplant rejection (e.g., kidney, liver, heart, lung, pancreas, bonemarrow, cornea, small bowel, skin allografts, skin homografts,heterografts, and/or cells derived from such organs), and skinconditions including, but not limited to scar tissue formation, eczema,atopic dermatitis, contact dermatitis, urticaria, schleroderma,scleraclerma, and psoriasis. The inventive compounds also may be used totreat allergies and respiratory conditions, including asthma, acuterespiratory distress syndrome, hayfever, allergic rhinitis, and anychronic pulmonary inflammatory disease such as chronic obstructivepulmonary disease. The compounds further may be used to treat steroidresistance in asthma and allergies.

Additionally, the inventive compounds may be used to treat inflammationassociated with autoimmune diseases including, but not limited to,systemic lupus erythematosis, Addison's disease, autoimmunepolyglandular disease (also known as autoimmune polyglandular syndrome),and Graves' disease. The inventive compounds may be used to infectiousdiseases such as sepsis, septic shock, Shigellosis, and HeliobacterPylori.

The compounds may be used to treat viral diseases including herpessimplex type 1 (HSV-1), herpes simplex type 2 (HSV-2), cytomegalovirus,Epstein-Barr, human immunodeficiency virus (HIV), acute hepatitisinfection (including hepatitis A, hepatits B, and hepatitis C), HIVinfection and CMV retinitis, AIDS, ARC or malignancy, and herpes.

The inventive compounds also may be used to treat angiogenic disordersincluding solid tumors, ocular neovasculization, and infantilehaemangiomas.

In addition, p38 inhibitors of this invention inhibit the expression ofinducible pro-inflammatory proteins such as prostaglandin endoperoxidesynthase-2 (PGHS-2), also referred to as cyclooxygenase-2 (COX-2).Accordingly, additional conditions that may be treated with theinventive compounds include edema, analgesia and pain, such asneuromuscular pain, headache, pain caused by cancer or surgery, dentalpain and arthritis pain. In view of their COX-2 inhibitory activity, theinventive compounds also may be used to treat cancer including withoutlimitation epithelial cancer and adenocarcinoma.

Additionally, the compounds of this invention are useful to treatischemia, including ischemia resulting from vascular occlusion, cerebralinfarction, stroke, and related cerebral vascular diseases (includingcerebrovascular accident and transient ischemic attack). Accordingly,the compounds may be used to treat myocardial infarction, coronaryartery disease, non-Q wave MI, congestive heart failure, ventricularhypertrophy, cardiac arrhythmias, unstable angina, chronic stableangina, Prinzmetal's angina, high blood pressure, intermittentclaudication, silent ischemia, cardiac hypertrophy, and peripheralocclusive arterial disease (e.g., peripheral arterial disease, criticalleg ischemia, prevention of amputation, and prevention of cardiovascularmorbidity such as MI, stroke or death).

Additionally, in view of their activity in treating ischemia, thecompounds of the invention may be useful to treat symptoms orconsequences occurring from thrombosis, atherosclerosis, peripheralarterial disease, and thrombotic or thromboembolic symptoms orconsequences associated with and/or caused by one or more of thefollowing: thromboembolic stroke (including that resulting from atrialfibrillation or from ventricular or aortic mural thrombus), venousthrombosis (including deep vein thrombosis), arterial thrombosis,cerebral thrombosis, pulmonary embolism, cerebral embolism,thrombophilia (e.g., Factor V Leiden, and homocystinenimia), coagulationsyndromes and coagulopathies (e.g., disseminated intravascularcoagulation), restenosis (e.g., following arterial injury inducedendogenously or exogenously), atrial fibrillation, and ventricularenlargement (including dilated cardiac myopathy and heart failure). Thecompounds of the invention also may be used to treat symptoms orconsequences of atherosclerotic diseases and disorders, such asatherosclerotic vascular disease, atherosclerotic plaque rupture,atherosclerotic plaque formation, transplant atherosclerosis, andvascular remodeling atherosclerosis. The compounds of the inventionfurther may be used to treat symptoms or consequences of thrombotic orthromboembolic conditions associated with cancer, surgery, inflammation,systematic infection, artificial surfaces (such as stents, bloodoxygenators, shunts, vascular access ports, vascular grafts, artificialvalves, etc.), interventional cardiology such as percutaneoustransluminal coronary angioplasty (PTCA), immobility, medication (suchas oral contraceptives, hormome replacement therapy, and heparin),pregnancy and fetal loss, and diabetic complications includingretinopathy, nephropathy, and neuropathy.

The compounds of the present invention may be used for the preservationof tissue, for example, the preservation of tissue as relates to organtransplantation and surgical manipulation. The compounds may be used totreat diseases or disorders in other tissues or muscles that areassociated with ischemic conditions and/or to enhance the strength orstability of tissue and muscles. For example, the compounds may be usedto treat muscle cell damage and necrosis and/or to enhance athletes'performance.

Additional diseases and disorders that may be treated with the inventivecompounds include irritable bowel syndrome, leukemia, CNS disordersassociated with cerebral ischemia, such as cerebral infarction, cerebraledema and the like, and diseases associated with proliferation of smoothmuscle cells, mesangial cells, and fibroblasts. Such diseases includerenal fibrosis, hepatic fibrosis, prostate hypertrophy, and pulmonaryfibrosis.

The inventive compounds also may be used to treat veterinary viralinfections, such as lentivirus infections, including, but not limitedto, equine infectious anemia virus; or retro virus infections, includingfeline immunodeficiency virus, bovine immunodeficiency virus, and canineimmunodeficiency virus.

When the terms “p38 associated condition” or “p38 associated disease ordisorder” are used herein, each is intended to encompass all of theconditions identified above as if repeated at length, as well as anyother condition that is modulated by p38 kinase activity.

The present invention thus provides methods for treating suchconditions, comprising administering to a subject in need thereof aneffective amount of at least one compound of Formula (I), or apharmaceutically-acceptable salt, hydrate, or prodrug thereof. Themethods of treating p38 kinase-associated conditions may compriseadministering compounds of Formula (I) alone or in combination with eachother and/or other suitable therapeutic agents such as anti-inflammatorydrugs, antibiotics, anti-viral agents, anti-oxidants, cholesterol/lipidlowering agents, anti-tumor agents including antiproliferative agents,and agents used to treat ischemia.

Examples of suitable other anti-inflammatory agents with which theinventive compounds may be used include aspirin, cromolyn, nedocromil,theophylline, zileuton, zafirlukast, monteleukast, pranleukast,indomethacin, and lipoxygenase inhibitors; non-steroidalantiinflammatory drugs (NSAIDs) (such as ibuprofen and naproxin); TNF-αinhibitors (such as tenidap and rapamycin or derivatives thereof), orTNF-α antagonists (e.g., infliximab, enbrel, D2E7, OR₁₃₈₄), cytokinemodulators (e.g. TNF-alpha converting enzyme [TACE] inhibitors,Interleukin-1 converting enzyme (ICE) inhibitors, Interleukin-1 receptorantagonists), prednisone, dexamethasone, Enbrel®, cyclooxygenaseinhibitors (i.e., COX-1 and/or COX-2 inhibitors such as Naproxen®,Celebrex®, or Vioxx®), CTLA4-Ig agonists/antagonists (LEA29Y), CD40ligand antagonists, IMPDH inhibitors (such as mycophenolate [CellCept®]and VX-497), integrin antagonists, alpha-4 beta-7 integrin antagonists,cell adhesion inhibitors, interferon gamma antagonists, ICAM-1,prostaglandin synthesis inhibitors, budesonide, clofazimine, CNI-1493,CD4 antagonists (e.g., priliximab), other p38 mitogen-activated proteinkinase inhibitors, protein tyrosine kinase (PTK) inhibitors, IKKinhibitors, therapies for the treatment of irritable bowel syndrome(e.g., Zelmac®, Zelnorm®, and Maxi-K® openers such as those disclosed inU.S. Pat. No. 6,184,231 B1), or other NF-κB inhibitors (such calphostin,CSAIDs, and quinoxalines as disclosed in U.S. Pat. No. 4,200,750);corticosteroids (such as beclomethasone, triamcinolone, budesonide,fluticasone, flunisolide, dexamethasone, prednisone, and dexamethasone);disassociated steroids; chemokine receptor modulators (including CCR1,CCR2, CCR3, CCR4, and CXCR2 receptor antagonists); secretory andcytosolic phospholipase A2 inhibitors, VLA4 antagonists,glucocorticoids, salicylates, nitric oxide, and otherimmunosuppressants; and nuclear translocation inhibitors, such asdeoxyspergualin (DSG).

To treat pain, the inventive compounds may be used in combination withaspirin, NSAIDs, or with 5-HT 1 receptor agonists such as buspirone,sumitriptan, eletriptan or rizatriptan.

Examples of suitable antibiotics with which the inventive compounds maybe used include β-lactams (e.g., penicillins, cephalosporins andcarbopenams); β-lactam and lactamase inhibitors (e.g., augamentin);aminoglycosides (e.g., tobramycin and streptomycin); macrolides (e.g.,erythromycin and azithromycin); quinolones (e.g., cipro and tequin);peptides and deptopeptides (e.g. vancomycin, synercid and daptomycin)metabolite-based anti-biotics (e.g., sulfonamides and trimethoprim);polyring systems (e.g., tetracyclins and rifampins); protein synthesisinhibitors (e.g., zyvox, chlorophenicol, clindamycin, etc.); andnitro-class antibiotics (e.g., nitrofurans and nitroimidazoles).

Examples of suitable antiviral agents for use with the inventivecompounds include nucleoside-based inhibitors, protease-basedinhibitors, and viral-assembly inhibitors.

Examples of suitable anti-osteoporosis agents for use in combinationwith the compounds of the present invention include alendronate,risedronate, PTH, PTH fragment, raloxifene, calcitonin, RANK ligandantagonists, calcium sensing receptor antagonists, TRAP inhibitors,selective estrogen receptor modulators (SERM) and AP-1 inhibitors.

Examples of suitable anti-oxidants for use in combination with thecompounds of the present invention include lipid peroxidation inhibitorssuch as probucol, BO-653, Vitamin A, Vitamin E, AGI-1067, and α-lipoicacid.

A further use of the compounds of this invention is in combination withsteriodal or non-steroidal progesterone receptor agonists (“PRA”), suchas levonorgestrel, medroxyprogesterone acetate (MPA).

The inventive compounds also may be used in combination withanti-diabetic agents, such as biguanides (e.g. metformin), glucosidaseinhibitors (e.g. acarbose), insulins (including insulin secretagogues orinsulin sensitizers), meglitinides (e.g. repaglinide), sulfonylureas(e.g., glimepiride, glyburide and glipizide), biguanide/glyburidecombinations (e.g., glucovance), thiozolidinediones (e.g. troglitazone,rosiglitazone and pioglitazone), PPAR-alpha agonists, PPAR-gammaagonists, PPAR alpha/gamma dual agonists, SGLT2 inhibitors, inhibitorsof fatty acid binding protein (aP2) such as those disclosed in U.S. Ser.No. 09/519,079 filed Mar. 6, 2000 and assigned to the present assignee,glucagon-like peptide-1 (GLP-1), glucagon phosphorylase, and dipeptidylpeptidase IV (DP4) inhibitors.

In addition, the compounds may be used with agents that increase thelevels of cAMP or cGMP in cells for a therapeutic benefit. For example,the compounds of the invention may have advantageous effects when usedin combination with phosphodiesterase inhibitors, including PDE1inhibitors (such as those described in Journal of Medicinal Chemistry,Vol. 40, pp. 2196-2210 [1997]), PDE2 inhibitors, PDE3 inhibitors (suchas revizinone, pimobendan, or olprinone), PDE4 inhibitors (such asrolipram, cilomilast, or piclamilast), PDE7 inhibitors, or other PDEinhibitors such as dipyridamole, cilostazol, sildenafil, denbutyline,theophylline (1,2-dimethylxanthine), ARIFLO™ (i.e.,cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid), arofyline, roflumilast, C-11294A, CDC-801, BAY-19-8004,cipamfylline, SCH351591, YM-976, PD-189659, mesiopram, pumafentrine,CDC-998, IC-485, and KW-4490.

The inventive compounds may also be useful in combination withanticancer strategies and chemotherapies such as taxol and/or cisplatin.The compounds may be used in conjunction with antitumor agents such aspaclitaxel, adriamycin, epithilones, cisplatin, and carboplatin.

In view of their usefulness in treating ischemia, the inventivecompounds may be used in combination with agents for inhibitingF₁F₀-ATPase, including efrapeptin, oligomycin, autovertin B, azide, andcompounds described in U.S. patent application Ser. No. 10/315,818,filed Dec. 10, 2001 and assigned to the present assignee; -alpha- orbeta-adrenergic blockers (such as propranolol, nadolol, carvedilol, andprazosin), or -β-adrenergic agonists (such as albuterol, terbutaline,formoterol, salmeterol, bitolterol, pilbuterol, and fenoterol);antianginal agents such as nitrates, for example, sodium nitrates,nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, andnitrovasodilators; antiarrhythmic agents including Class I agents (suchas propafenone); Class II agents (propranolol); Class III agents (suchas sotalol, dofetilide, amiodarone, azimilide and ibutilide); Class IVagents (such as diltiazem and verapamil); K⁺ channel modulators such asI_(Ach) inhibitors and inhibitors of the K_(v)1 subfamily of K⁺ channelopeners such as I_(Kur) inhibitors (e.g., compounds disclosed in U.S.application Ser. No. 09/729,731, filed Dec. 5, 2000); and gap-junctionmodulators such as connexions; anticoagulant or antithrombotic agentsincluding aspirin, warfarin, ximelagtran, low molecular weight heparins(such as lovenox, enoxaparain, and dalteparin), anti-platelet agentssuch as GPIIb/GPIIIa blockers, (e.g., abciximab, eptifibatide, andtirofiban), thromboxane receptor antagonists (e.g., ifetroban), P2Y₁ andP2Y₁₂ antagonists (e.g., clopidogrel, ticlopidine, CS-747, andaspirin/clopidogrel combinations), and Factor Xa inhibitors (e.g.,fondaprinux); and diuretics such as sodium-hydrogen exchange inhibitors,chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone,furosemide, musolimine, bumetanide, triamtrenene, and amiloride.

Additionally, the inventive compounds may be used in combination withlipid profile modulators and antiatherosclerotic agents includingHMG-CoA reductase inhibitors (e.g., pravastatin, simvastatin,atorvastatin, fluvastatin, cerivastatin, AZ4522, itavastatin[Nissan/Kowa]), ZD-4522 (a.k.a. rosuvastatin, atavastatin orvisastatin), pravachol, squalene synthetase inhibitors, fibrates, bileacid sequestrants (such as questran), niacin and niacin/statincombinations, lipooxygenase inhibitors, ileal Na⁺/bile acidcotransporter inhibitors, ACAT1 inhibitors, ACAT2 inhibitors, dualACAT1/2 inhibitors, microsomal triglyceride transport protein inhibitors(such as disclosed in U.S. Pat. Nos. 5,739,135, 5,712,279 and5,760,246), cholesterol absorption inhibitors (such as Zetia®),cholesterol ester transfer protein inhibitors (e.g., CP-529414),PPAR-delta agonists, PPAR-alpha agonists, dual PPAR-alpha/deltaagonists, LXR-alpha agonists, LXR-beta agonists, LXR dual alpha/betaagonists, and SCAP modulators.

The combination of the inventive compounds with other therapeutic agentsmay prove to have additive and synergistic effects. The combination maybe advantageous to increase the efficacy of the administration ordecrease the dosage to reduce possible side-effects.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art. In the methodsof the present invention, such other therapeutic agent(s) may beadministered prior to, simultaneously with, or following theadministration of the inventive compounds.

The present invention also provides pharmaceutical compositions capableof treating p38-kinase associated conditions, including TNF-α, IL-1,and/or IL-8 mediated conditions, as described above. The inventivecompositions may contain other therapeutic agents as described above.Pharmaceutical compositions may be formulated by employing conventionalsolid or liquid vehicles or diluents, as well as pharmaceuticaladditives of a type appropriate to the mode of desired administration(e.g., excipients, binders, preservatives, stabilizers, flavors, etc.)according to techniques such as those well known in the art ofpharmaceutical formulations.

The compounds of Formula (I) may be administered by any means suitablefor the condition to be treated, which may depend on the need forsite-specific treatment or quantity of drug to be delivered. Topicaladministration is generally preferred for skin-related diseases, andsystematic treatment preferred for cancerous or pre-cancerousconditions, although other modes of delivery are contemplated. Forexample, the compounds may be delivered orally, such as in the form oftablets, capsules, granules, powders, or liquid formulations includingsyrups; topically, such as in the form of solutions, suspensions, gelsor ointments; sublingually; bucally; parenterally, such as bysubcutaneous, intravenous, intramuscular or intrasternal injection orinfusion techniques (e.g., as sterile injectable aq. or non-aq.solutions or suspensions); nasally such as by inhalation spray;topically, such as in the form of a cream or ointment; rectally such asin the form of suppositories; or liposomally. Dosage unit formulationscontaining non-toxic, pharmaceutically acceptable vehicles or diluentsmay be administered. The compounds may be administered in a formsuitable for immediate release or extended release. Immediate release orextended release may be achieved with suitable pharmaceuticalcompositions or, particularly in the case of extended release, withdevices such as subcutaneous implants or osmotic pumps.

Exemplary compositions for topical administration include a topicalcarrier such as PLASTIBASE® (mineral oil gelled with polyethylene).

Exemplary compositions for oral administration include suspensions whichmay contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which may contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The inventive compounds may also be orally delivered bysublingual and/or buccal administration, e.g., with molded, compressed,or freeze-dried tablets. Exemplary compositions may includefast-dissolving diluents such as mannitol, lactose, sucrose, and/orcyclodextrins. Also included in such formulations may be high molecularweight excipients such as celluloses (AVICEL®) or polyethylene glycols(PEG); an excipient to aid mucosal adhesion such as hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodiumcarboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer (e.g.,GANTREZ®); and agents to control release such as polyacrylic copolymer(e.g., CARBOPOL 934®). Lubricants, glidants, flavors, coloring agentsand stabilizers may also be added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions which may contain, for example, benzyl alcohol orother suitable preservatives, absorption promoters to enhance absorptionand/or bioavailability, and/or other solubilizing or dispersing agentssuch as those known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which may contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid.

Exemplary compositions for rectal administration include suppositorieswhich may contain, for example, suitable non-irritating excipients, suchas cocoa butter, synthetic glyceride esters or polyethylene glycols,which are solid at ordinary temperatures but liquefy and/or dissolve inthe rectal cavity to release the drug.

The effective amount of a compound of the present invention may bedetermined by one of ordinary skill in the art, and includes exemplarydosage amounts for a mammal of from about 0.05 to 100 mg/kg of bodyweight of active compound per day, which may be administered in a singledose or in the form of individual divided doses, such as from 1 to 4times per day. It will be understood that the specific dose level andfrequency of dosage for any particular subject may be varied and willdepend upon a variety of factors, including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the species, age, body weight, general health, sex and diet ofthe subject, the mode and time of administration, rate of excretion,drug combination, and severity of the particular condition. Preferredsubjects for treatment include animals, most preferably mammalianspecies such as humans, and domestic animals such as dogs, cats, horses,and the like. Thus, when the term “patient” is used herein, this term isintended to include all subjects, most preferably mammalian species,that are affected by mediation of p38 enzyme levels.

Compounds of within the scope of formula (I) may be tested for activityas inhibitors of p38α/β enzymes and TNF-α using the assays describedbelow, or variations thereof that are within the level ordinary skill inthe art. Compounds described in the examples herein have shown activityas inhibitors of p38α/β enzymes and TNF-α.

Biological Assays

Generation of p38 Kinases

cDNAs of human p³⁸α, β and γ isozymes are cloned by PCR. These cDNAs canbe subcloned in the pGEX expression vector (Pharmacia). GST-p38 fusionprotein is expressed in E. Coli and purified from bacterial pellets byaffinity chromatography using glutathione agarose. p38 fusion protein isactivated by incubating with constitutively active MKK6. Active p38 isseparated from MKK6 by affinity chromatography. Constitutively activeMKK6 is generated according to Raingeaud et al. [Mol. Cell. Biol.,1247-1255 (1996)].

TNF-α Production by LPS-Stimulated PBMCs

Heparinized human whole blood is obtained from healthy volunteers.Peripheral blood mononuclear cells (PBMCs) are purified from human wholeblood by Ficoll-Hypaque density gradient centrifugation and resuspendedat a concentration of 5×10⁶/ml in assay medium (RPMI medium containing10% fetal bovine serum). 50 ul of cell suspension is incubated with 50ul of test compound (4× concentration in assay medium containing 0.2%DMSO) in 96-well tissue culture plates for 5 minutes at RT. 100 ul ofLPS (200 ng/ml stock) is then added to the cell suspension and the plateis incubated for 6 hours at 37° C. Following incubation, the culturemedium is collected and stored at −20° C. TNF-α concentration in themedium is quantified using a standard ELISA kit (Pharmingen-San Diego,Calif.). Concentrations of TNF-α and IC₅₀ values for test compounds(concentration of compound that inhibited LPS-stimulated TNF-αproduction by 50%) are calculated by linear regression analysis.

p38 Assay

The assays are performed in V-bottomed 96-well plates. The final assayvolume is 60 μl prepared from three 20 μl additions of enzyme,substrates (MBP and ATP) and test compounds in assay buffer (50 mM TrispH 7.5, 10 mM MgCl₂, 50 mM NaCl and 1 mM DTT). Bacterially expressed,activated p38 is pre-incubated with test compounds for 10 min. prior toinitiation of reaction with substrates. The reaction is incubated at 25°C. for 45 min. and terminated by adding 5 μl of 0.5 M EDTA to eachsample. The reaction mixture is aspirated onto a pre-wet filtermat usinga Skatron Micro96 Cell Harvester (Skatron, Inc.), then washed with PBS.The filtermat is then dried in a microwave oven for 1 min., treated withMeltilLex A scintillation wax (Wallac), and counted on a Microbetascintillation counter Model 1450 (Wallac). Inhibition data are analyzedby nonlinear least-squares regression using Prizm (GraphPadSoftware).The final concentration of reagents in the assays are ATP, 1 μM;[γ-³³P]ATP, 3 nM,; MBP (Sigma, #M1891), 2 μg/well; p38, 10 nM; and DMSO,0.3%.

TNF-α Production by LPS-Stimulated Mice

Mice (Balb/c female, 6-8 weeks of age, Harlan Labs; n=8/treatment group)are injected intraperitoneally with 50 ug/kg lipopolysaccharide (LPS; Ecoli strain 0111:B4, Sigma) suspended in sterile saline. Ninety minuteslater, mice are sedated by CO₂:O₂ inhalation and a blood sample wasobtained. Serum is separated and analyzed for TNF-alpha concentrationsby commercial ELISA assay per the manufacturer's instructions (R&DSystems, Minneapolis, Minn.).

Test compounds are administered orally at various times before LPSinjection. The compounds are dosed either as suspensions or as solutionsin various vehicles or solubilizing agents.

Abbreviations

For ease of reference, the following abbreviations are employed herein,including the methods of preparation and Examples that follow:

-   Ph=phenyl-   Bz=benzyl-   t-Bu=tertiary butyl-   Me=methyl-   Et=ethyl-   Pr=propyl-   Iso-P or iPr=isopropyl-   MeOH=methanol-   EtOH=ethanol-   EtOAc=ethyl acetate-   Boc=tert-butyloxycarbonyl-   DCM=dichloromethane-   DCE=1,2-dichloroethane-   DMF=N,N-dimethyl formamide-   DMF-DMA=N,N-dimethyl formamide dimethyl acetal-   DMSO=dimethyl sulfoxide-   TFA=trifluoroacetic acid-   THF=tetrahydrofuran-   HATU=O-(7-Azabenzotriazol-1-yl-N,N,N′,N′-tetramethyluronim    hexafluorophosphate-   BOP=benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium    hexafluorophosphate-   DPPA=diphenylphosphoryl azide-   KOH=potassium hydroxide-   K₂CO₃=potassium carbonate-   POCl₃=phosphorous oxychloride-   EDC or EDCI=1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide    hydrochloride-   DIPEA=diisopropylethylamine-   HOBt=1-hydroxybenzotriazole hydrate-   m-CPBA=m-chloroperbenzoic acid-   NaH=sodium hydride-   NaOH=sodium hydroxide-   Pd=palladium-   Pd/C=palladium on carbon-   min=minute(s)-   h or hr=hour(s)-   L=liter-   mL=milliliter-   μL=microliter-   g=gram(s)-   mg=milligram(s)-   mol=moles-   mmol=millimole(s)-   meq=milliequivalent-   RT or rt=room temperature-   ret. t.=HPLC retention time (minutes)-   sat or sat'd=saturated-   aq.=aqueous-   TLC=thin layer chromatography-   HPLC=high performance liquid chromatography-   RP HPLC=reverse phase HPLC-   Prep HPLC=preparative reverse phase HPLC-   LC/MS=high performance liquid chromatography/mass spectrometry-   MS=mass spectrometry-   NMR=nuclear magnetic resonance-   mp=melting point

HPLC Conditions: YMC S5 ODS 4.6×50 mm Ballistic column, 4 mL/min flowrate, 4 min. linear gradient elution (Start solvent % B=0; Final solvent% B=100), solvent A=10% MeOH/90% H₂O/0.2% H₃PO₄. Solvent B=90% MeOH/10%H₂O/0.2% H₃PO₄.

The above HPLC condition is used throughout the specification exceptwhere the superscript a is used, in which case the following conditionsare used: Column: Phenomenex 4.6×30 mm; Flow rate: 5 mL/min; Gradienttime: 2 min with 1 min hold; Detection wave length: 220 nm; Startingsolvent: 10% MeOH-90% H2O-0.1% TFA; and Final solvent: 90% MeOH-10%H2O-0.1% TFA.

Microwave Chemistry: Microwave reactions were performed using thecommercially available Smith Synthesizer from Personal Chemistry. Thisreactor allows for precise control over reaction temperatures and timesand greater than atmospheric pressures.

The invention will now be further described by the following workingexamples, which are preferred embodiments of the invention. HPLCpurifications were done on C18 reverse phase (RP) columns using waterMeOH mixtures and TFA as buffer solution. These examples areillustrative rather than limiting. There may be other embodiments thatfall within the spirit and scope of the invention as defined by theappended claims.

EXAMPLE 1

Step A:

To a solution of 1-phenyl-5-propyl-1H-pyrazole-4-carbonyl chloride (245mg, 0.99 mmol) in THF (4 mL), at −78° C. was added LAH (1 M, 3 mL, 3.0mmol). The reaction was stirred for 1 hr at −78° C., then sat. aq. NH₄Cland water were added and the product was extracted with EtOAc to afford(1A) as a yellow gel (228 mg).Step B:

A mixture of (1A) (700 mg, 3.2 mmol) and MnO₄ (1.36 g, 194.4 mmol) inTHF (10 ml) was stirred at RT overnight. The solution was filtered andconcentrated to afford (1B) as a yellow gel (598 mg).

Step C:

To a solution of (1B) (83 mg, 0.20 mmol) and3-amino-N-cyclopropyl-4-methyl-benzamide hydrochloride (45 mg, 0.20mmol) in DCM (2 mL) at RT was added TFA (0.5 mL). After stirring for 30min., Et₃SiH (0.5 mL) was added and stirring continued for 2 hr. Thereaction was quenched with sat. aq. NaHCO₃, stirring for 10 min, thenextracted with EtOAc, and concentrated to afford Example 1 as a whitesolid after re-crystallization from DCM (0.032 g, 41%). HPLC ret. t.(min): 3.05, MW: 388.5, LCMS[M+H]⁺=389.1.

EXAMPLES 2 TO 16

The following examples shown in Table 1 were prepared in a manneranalogous to Example 1. In one or more examples herein, aldehydeintermetiate (1B) can be reacted with methyl magnesium bromide followedby oxidation with MnO₂ to afford a ketone, which subsequently mayundergo reductive amination as described in Example 1 to give thecompound of Formula (I). TABLE 1 Ex. No. Structure HPLC time (min.) MS(M⁺)  2

3.30 416.1  3

2.30 375.1  4

3.33 499.2  5

2.60 432.2  6

2.94 407.2  7

4.08 440.1  8

3.30 346.2  9

2.79 465.3 10

3.79 357.2 11

2.84 442.2 12

2.88 366.2 13

3.67 458.2 14

2.58 332.1 15

2.09 332.1 16

2.53 331.1

EXAMPLE 17

Step A:

To a solution of (1-phenyl-5-propyl-1H-pyrazol-4-yl)-methanol (1A) (244mg, 1.13 mmol) in DCM (8 mL) was added POBr₃ (323 mg, 1.13 mmol) and thereaction was stirred at RT overnight. The solution was concentrated toafford (17A) (0.300 g), which was used in the next step without furtherpurification.

Step B:

A solution of (17A) (0.050 g, 0.18 mmol) and DIPEA (0.100 mL) in THF (2mL) was stirred for 15 min., thenN-cyclopropyl-3-hydroxy-4-methyl-benzamide (0.020 g, 0.10 mmol),additional DIPEA (0.20 mL), and K₂CO₃ (0.32 g, 2.3 mmol) was added andstirring continued for 4 hr. NaH (60%, 0.008 g, 0.2 mmol) was added andthe reaction was stirred for 2 hr. Water and sat. aq. NaHCO₃ were addedand the product extracted with EtOAC. Purification by Prep HPLC afforded(17) as a yellow gel (0.0031 g). HPLC ret. t. (min): 3.85, MW: 389.5,LCMS[M+H]⁺=390.2.

EXAMPLE 18

Step A:

To a solution of 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (0.87g, 4.63 mmol) in toluene (20 mL) was added Et₃N (1.7 mL, 11.6 mmol) andDPPA (2.54 mL, 11.6 mmol). The reaction was heated to 50° C. for 24 hr,tert-butyl alcohol (1.47 mL, 13.9 mmol) was added and stirring continuedat 80° C. overnight. Water was added, and the reaction was cooled to RTover 1 hr. The intermediate carbamate was extracted with EtOAc. Afterconcentration of the organics, a yellow gel (3 g) was obtained, whichwas used without further purification. The carbamate intermediate wasdissolved in THF (10 mL) and HCl/Et₂O (10 mL) was added. After stirringfor 2 hr at 35° C. the solvents were evaporated. DCM was added to thecrude residue with vigorous stirring and the resulting precipitate wascollected by filtration to afford (18A) as a white solid (268 mg).

Step B:

To a solution of pyrazole (18A) (0.025 g, 0.14 mmol) in DCM (2 mL) wasadded isonicotinoyl chloride hydrochloride (0.025 g, 0.14 mmol) andDIPEA (0.054 mL, 0.38 mmol). After stirring at RT overnight, thereaction was quenched with water and extracted with EtOAc. The organicextracts were washed with brine, dried over MgSO₄, filtered, andconcentrated to afford (18) as a yellow solid (0.028 g). HPLC ret. t.(min): 1.75, MW: 278.3, LCMS[M+H]⁺=279.2.

EXAMPLES 19 TO 43

The following examples shown in Table 2 were prepared in a manneranalogous to Example 18. TABLE 2 Ex. No. Structure HPLC time (min.) MS(M⁺) 19

2.89 336.2 20

3.10 496.2 21

2.72 363.2 22

2.80 337.2 23

2.68 303.1 24

1.85 279.1 25

2.66 303.2 26

2.04 322.1 27

1.80 289.2 28

2.57 322.1 29

2.63 310.1 30

2.87 360.0 31

2.57 328.1 32

2.54 292.1 33

1.24 265.2 34

2.46 292.1 35

2.95 332.0 36

2.24 300.1 37

2.74 279.2 38

2.62 322.2 39

2.60 314.2 40

2.81 306.2 41

2.88 379.2 42

3.23 404.1 43

421.46

1. A compound having the formula (I),

wherein: ring G is phenyl; W is —CH(R₈)NH—, wherein R₈ is hydrogen oralkyl; R₁ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl,heterocyclo or substituted heterocyclo; R₂ is hydrogen, alkyl, orsubstituted alkyl; R₃ is hydrogen, C₁₋₄alkyl, or substituted C₁₋₄alkyl;R₄ is hydrogen, C₁₋₄alkyl, or substituted C₁₋₄alkyl; X is —C═O)NH—; R₆is hydrogen, alkyl or substituted alkyl, alkoxy or substituted alkoxy,phenoxy or substituted phenoxy, cycloalkyl or substituted cycloalkyl,heterocycle or substituted heterocycle, aryl or substituted aryl; and mis 0; or a pharmaceutically-acceptable salt, hydrate, solvent, isomer,or prodrug thereof.
 2. A compound according to claim 1, having theformula,

or a pharmaceutically acceptable salt or solvate thereof, wherein R₉ isselected from alkyl or substituted alkyl, trifluoromethyl,trifluoromethoxy, halogen, cyano, nitro, OH, OR₁₀, SR₁₀, and S(═O)₂R₁₀,wherein R₁₀ is lower alkyl; and n is 0, 1, 2 or
 3. 3. The compound ofclaim 2, wherein: Q is phenyl; R₆ is C₁-C₄ alkyl or substituted C₁-C₄alkyl, cycloalkyl or substituted cycloalkyl; R₂ is lower alkyl oralkylamino; and R₄ is lower alkyl.
 4. The compound of claim 1, wherein:R₁ is C₁-C₄ alkyl or substituted C₁-C₄ alkyl, cycloalkyl or substitutedcycloalkyl, heterocycle or substituted heterocycle, aryl or substitutedaryl; R₆ is cyclopropyl; R₂ is hydrogen, trifluoromethyl, C₁-C₄ alkyl orsubstituted C₁-C₄ alkyl; and R₄ is lower alkyl
 5. The compound of claim4, wherein R₃ is hydrogen and R₄ is methyl.
 6. The compound of claim 1,wherein R₃ is hydrogen and R₄ is methyl.
 7. A compound according toclaim 1, wherein R₁ is selected from:

and

wherein R₃₀, R₃₁, R₃₂, R₃₃ and R₃₄ are selected from hydrogen, halogen,cyano, trifluoromethyl, trifluoromethoxy, C₁₋₄alkyl, O(C₁₋₄alkyl),nitro, and/or SO₂CH₃; and R₅₀ is hydrogen, alkyl, or arylalkyl; and n isat each occurrence independently selected from 0-3; and/orpharmaceutically-acceptable salts, prodrugs, solvates, isomers, and/orhydrates thereof.
 8. A compound according to claim 1, wherein R₁ isoptionally-substituted aryl or heteroaryl; R₂ is hydrogen, lower alkyl,haloalkyl, or trifluoromethyl; R₃ is hydrogen or methyl; R₄ is methyl;R₆ is lower alkyl or cyclopropyl; and/or pharmaceutically-acceptablesalts, prodrugs, solvates, isomers, and/or hydrates thereof.
 9. Thecompound of claim 8, wherein R₃ is hydrogen.
 10. A pharmaceuticalcomposition comprising at least one compound according to claim 1 and apharmaceutically-acceptable carrier or diluent.